ABSTRACT: CORE A The central hypothesis of this Program Project Grant is that HDL?s platform protein, apoA-I, is a conformationally dynamic scaffold that facilitates interactions among other HDL proteins and lipid remodeling factors that exert potent biological effects on the artery wall. Our objective is to empower a multidisciplinary team to understand, in unprecedented detail, HDL?s structure, function, assembly and dynamics, including the molecular mechanisms that enable apoA-I to function as a platform. Our proposed research program centers on three topics: Project 1: Structural basis of HDL assembly ?Jere Segrest, Project Leader (UAB); Project 2: Structural basis of HDL maturation ?W. Sean Davidson, Project Leader (U. Cincinnati); Project 3: Structural basis of HDL function ? Jay Heinecke, Project Leader (U. Washington). These three topics involve the dynamic interactions among four world-class scientists with unique (and complementary) areas of expertise all studying HDL, a unique collaboration unlikely to exist at any single institution and rare in science and in the HDL field. Each project has proposed several collaborative studies among projects that would not be possible in the absence of a PPG. All projects will make extensive use of four Cores, which are key components of the PPG: CORE A: Administration?Jere Segrest (UAB), Core Leader; CORE B: Computational biology?Martin Jones (UAB), Core Leader; CORE C: HDL quantitation and function?Tomas Vaisar, Core Leader (U. Washington); CORE D: Protein production and interaction?W. Sean Davidson, Core Leader (U. Cincinnati). The Administrative Core will direct the program, evaluate scientific progress, facilitate interactions among investigators, and provide administrative and budgetary support to the Program as a whole and individual Project Leaders and Core Leaders. Since this complicated PPG involves projects and cores at three separate institutions (UAB, U. Cincinnati, and U. Washington) and one additional co-investigator at a fourth institution (Lawrence Berkley Laboratories), we must establish robust mechanisms to ensure that our extensive interactions continue during the funding period, with appropriate outside advisory input and fiscal oversight. To achieve the required integration between investigators and institutions, we propose these specific aims: 1. Apply the latest in multi-investigator conferencing technology to exchange, across the continent, detailed research results and ideas in real time; 2. Establish mechanisms for document sharing, file management and maintenance of a common calendar for all investigators; 3. Coordinate and fund twice-yearly meetings of the PDs and co-Is; 4. Provide mechanisms for outside scientific input by establishing and coordinating meetings of External and Internal Advisory Committees and arranging for outside consultants; 5. Provide fiscal oversight to the projects and cores outside the Applicant Institution of UAB by issuing quarterly subcontracts to U. Cincinnati, U. Washington and Lawrence Berkley Laboratories, and by conducting quarterly reviews of their balances.